Clinical Research and Public Health
Abstract
Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 antibodies are used to induce an immune response against many types of tumors. However, ICIs often also induce autoimmune responses, referred to as immune-related adverse events (irAEs), which occur unpredictably and at varying levels of severity in ICI-treated patients. The immunologic factors that predispose patients to the development of severe irAE are largely unclear. Here, we utilized high dimensional mass cytometry immunophenotyping of longitudinal blood samples from patients with metastatic melanoma treated with combination anti-PD-1/CTLA4 ICI therapy in the context of a clinical trial to characterize alterations in immune profiles induced by combination ICI therapy and to identify immune features associated with development of severe irAEs. Deep T cell profiling highlighted that ICI therapy induces prominent expansions of activated, CD38hi CD4+ and CD8+ T cells, which are frequently bound by the therapeutic anti-PD-1 antibody, as well as substantial changes in regulatory T cell phenotypes. However, neither the baseline frequency nor the extent of expansion of these cell populations was associated with development of severe irAEs. Rather, single cell-association testing revealed naïve CD4+ T cell abundance pre-treatment as significantly associated with the development of severe irAEs. Biaxial gating of naïve CD4+ T cells confirmed a significant positive association of naïve CD4+ T cell proportion and development of a severe irAE and with the number of irAEs developed in this cohort. Results from this broad profiling study indicate the abundance of naïve CD4+ T cells as a predictive feature for the development of severe irAEs following combination anti-PD-1/CTLA4 ICI therapy.
Authors
Kathryne E. Marks, Alice Horisberger, Mehreen Elahee, Ifeoluwakiisi A. Adejoorin, Nilasha Ghosh, Michael A. Postow, Laura Donlin, Anne R. Bass, Deepak A. Rao
Abstract
BACKGROUND. Individuals with autoimmune diseases (AD) on immunosuppressants often have suboptimal responses to COVID-19 vaccine. We evaluated the efficacy and safety of additional COVID-19 vaccines in those treated with mycophenolate mofetil/mycophenolic acid (MMF/MPA), methotrexate (MTX), and B cell-depleting therapy (BCDT), including the impact of withholding MMF/MPA and MTX. METHODS. In this open-label, multicenter, randomized trial, 22 participants taking MMF/MPA, 26 taking MTX, and 93 treated with BCDT who had suboptimal antibody responses to initial COVID-19 vaccines (2 doses of BNT162b2 or mRNA-1273 or 1 dose of AD26.COV2.S) received an additional homologous vaccine. Participants taking MMF/MPA and MTX were randomized (1:1) to continue or withhold treatment around vaccination. The primary outcome was the change in anti-Wuhan-Hu-1 receptor-binding domain (RBD) concentrations at 4 weeks post-additional vaccination. Secondary outcomes included adverse events, COVID-19 , and AD activity through 48 weeks. RESULTS. Additional vaccination increased anti-RBD concentrations in participants taking MMF/MPA and MTX , irrespective of immunosuppressant withholding. BCDT-treated participants also demonstrated increased anti-RBD concentrations, albeit lower than MMF/MPA- and MTX-treated cohorts. COVID-19 occurred in 33% of participants; infections were predominantly mild and included only three non-fatal hospitalizations. Additional vaccination was well-tolerated, with low frequencies of severe disease flares and adverse events. CONCLUSION. Additional COVID-19 vaccination is effective and safe in individuals with ADs treated with immunosuppressants, regardless of whether MMF/MPA or MTX is withheld. TRIAL REGISTRATION. ClinicalTrials.gov (NCT05000216; registered August 6, 2021: https://clinicaltrials.gov/ct2/show/NCT05000216)
Authors
Meggan Mackay, Catriona A. Wagner, Ashley Pinckney, Jeffrey A. Cohen, Zachary S. Wallace, Arezou Khosroshahi, Jeffrey A. Sparks, Sandra Lord, Amit Saxena, Roberto Caricchio, Alfred H.J. Kim, Diane L. Kamen, Fotios Koumpouras, Anca D. Askanase, Kenneth Smith, Joel M. Guthridge, Gabriel Pardo, Yang Mao-Draayer, Susan Macwana, Sean McCarthy, Matthew A. Sherman, Sanaz Daneshfar Hamrah, Maria Veri, Sarah Walker, Kate York, Sara K. Tedeschi, Jennifer Wang, Gabrielle E. Dziubla, Mike Castro, Robin Carroll, Sandeep R. Narpala, Bob C. Lin, Leonid Serebryannyy, Adrian B. McDermott, William T. Barry, Ellen Goldmuntz, James McNamara, Aimee S. Payne, Amit Bar-Or, Dinesh Khanna, Judith A. James
Abstract
BACKGROUND. Cannabidiol (CBD) is increasingly used for pain management, including in transplant recipients with limited analgesic options. Its immunomodulatory effects in humans are not well defined at a single cell level at CBD steady state with concomitant tacrolimus treatment. METHODS. In a Phase 1 ex vivo study, peripheral blood mononuclear cells from 23 participants who received oral CBD (Epidiolex®) up to 5 mg/kg twice daily for 11 days were collected before CBD (pre-CBD) and at steady state (post-CBD). Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus (5 ng/mL). Pharmacodynamic responses were assessed using CellTiter-Glo® proliferation, single-cell/nucleus RNA sequencing, cytokine assays, and flow cytometry. Steady-state plasma concentrations of CBD were quantified via tandem mass spectrometry. RESULTS. We identified an increased proportion of T effector memory (TEM) cells post-cannabidiol (22% increase), which correlated with CBD plasma concentrations (R = 0.77, P-value = 0.01). Cannabidiol reduced proliferation of T (37% decrease) and CD70hi B (17% decrease) lymphocytes with additive immunosuppressive effects to tacrolimus. Single-cell RNA sequencing revealed reduced IL2 and TNF signaling and altered receptor–ligand networks in TEM cells. Post-cannabidiol cytokine assays revealed elevated proinflammatory IL-6 protein levels and anti-inflammatory IL-10 levels, with reduced TNF-α, LTA, and IL-2. In flow cytometry, the proportion of TEM and TEMRA increased post-cannabidiol with tacrolimus. CONCLUSION. Cannabidiol exhibits mixed immunomodulatory effects with pro- and anti-inflammatory signals. Understanding the clinical safety of cannabidiol use is important given the paucity of pain control options available for immunocompromised transplant populations.
Authors
Debora L. Gisch, Sachiko Koyama, Jumar Etkins, Gerald C. So, Daniel J. Fehrenbach, Jessica Bo Li Lu, Ying-Hua Cheng, Ricardo Melo Ferreira, Evan Rajadhyaksha, Kelsey McClara, Mahla Asghari, Asif A. Sharfuddin, Pierre C. Dagher, Laura M. Snell, Meena S. Madhur, Rafael B. Polidoro, Zeruesenay Desta, Michael T. Eadon
Abstract
BACKGROUND. Fecal Microbiota Transplantation (FMT) is the most effective therapy for recurrent Clostridioides difficile infection (rCDI), yet its mechanism of action remains poorly understood. METHODS. We report the results of a clinical trial of subjects undergoing FMT therapy for rCDI (n=16), analyzing colon biopsies, plasma, peripheral blood mononuclear cells, and stool at the time of FMT and two-month follow-up. Plasma and colon biopsy samples were also collected from healthy controls for comparison with rCDI patients. Microbiome composition, colonic gene expression, and immune changes were evaluated through high-throughput sequencing and immunoprofiling via flow cytometry. RESULTS. No subjects experienced recurrence at follow-up. FMT significantly altered the intestinal microbiome but had no significant impact on the systemic immune system. In contrast, FMT promoted broad changes in colonic transcriptional profiles compared to both pre-FMT and healthy control biopsies, inhibiting genes associated with pro-inflammatory signaling and upregulating type 2 immunity and proliferative pathways (Myc and mTORC1). FMT increased expression of IL-33 and the type 2 immune EGFR family ligand amphiregulin, potentially explaining upregulation of Myc and mTORC1 pathways. Spatial transcriptomics demonstrated that these changes were localized to the colonic epithelium. Comparison of transcriptional profiles with available single cell gene sets determined that post-FMT biopsies were enriched in signatures associated with proliferative cell types while repressing signatures of differentiated colonocytes. CONCLUSIONS. We conclude that FMT promotes proliferation of the colonic epithelium in rCDI patients, which may drive regeneration and protect against subsequent CDI. REGISTRATION. Clinicaltrials.gov NCT02797288. FUNDING. NIH grants R01 AI152477, R01 AI124214, and K23 AI163368.
Authors
G. Brett Moreau, Jiayi Tian, Nick R. Natale, Farha Naz, Mary K. Young, Uma Nayak, Mehmet Tanyüksel, Isaura Rigo, Gregory R. Madden, Mayuresh M. Abhyankar, Nicholas Hagspiel, Savannah Brovero, Mark Worthington, Brian Behm, Chelsea Marie, William A. Petri Jr., Girija Ramakrishnan
Abstract
BACKGROUND Among people living with HIV (PLWH), immunological nonresponders (INR) fail to adequately restore CD4+ T cell counts despite effective antiretroviral therapy (ART), placing them at greater risk for adverse outcomes and reduced vaccine efficacy. We aimed to study the robustness and longevity of vaccine-induced virus-specific cellular immune responses in INR.METHODS Virus-specific CD8+ T cell responses were analyzed in INR (CD4+ T cell count < 300 cells/μL) and immunological responders (IR) (CD4+ T cell count > 500 cells/μL), receiving ART, and HIV-uninfected controls following COVID-19 mRNA vaccination and infection. Virus-specific CD8+ T cells were characterized using peptide-loaded MHC I tetramer technology, after in vitro expansion and cytokine production assays. Virus-specific CD4+ T cells and IgG levels were determined by activation-induced marker (AIM) assay and ELISA, respectively.RESULTS We demonstrated that, while long-lasting virus-specific cellular immune responses were generated in INR, CD8+ T cell immunity remained limited compared with robust CD4+ T cell reactivity. CD8+ T cell responses in INR exhibited reduced breadth and frequency, accompanied by altered memory differentiation and suboptimal activation and effector response upon antigen exposure. This deficiency correlated with low CD4+ T cell counts, independent of other disease markers, highlighting the pivotal role of CD4+ T cells in orchestrating vaccine-induced immunity. Notably, repeated booster vaccinations enhanced virus-specific CD8+ T cell responses.CONCLUSION INR elicit limited vaccine-induced virus-specific CD8+ T cell immunity, but booster vaccinations can enhance these responses, suggesting better immune outcomes with tailored vaccination strategies.FUNDING Helmholtz Society, German Research Foundation, Federal Ministry of Education and Research.
Authors
Vivien Karl, Anne Graeser, Anastasia Kremser, Liane Bauersfeld, Florian Emmerich, Nadine Herkt, Siegbert Rieg, Susanne Usadel, Bertram Bengsch, Tobias Boettler, Hendrik Luxenburger, Christoph Neumann-Haefelin, Matthias C. Müller, Robert Thimme, Maike Hofmann
Abstract
BACKGROUND Accurate prognostic assays for COVID-19 represent an unmet clinical need. We sought to identify and validate early parsimonious transcriptomic signatures that accurately predict fatal outcomes.METHODS We studied 894 patients enrolled in the prospective, multicenter Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) with peripheral blood mononuclear cells (PBMC) and nasal swabs collected within 48 hours of admission. Host gene expression was measured with RNA-Seq. We trained parsimonious prognostic classifiers incorporating host gene expression, age, and SARS-CoV-2 viral load to predict 28-day mortality in 70% of the cohort. Classifier performance was determined in the remaining 30% and externally validated in a contemporary COVID-19 cohort (n = 137) with vaccinated patients.RESULTS Fatal COVID-19 was characterized by 4,189 differentially expressed genes in the peripheral blood. A COVID-specific 3-gene peripheral blood classifier (CD83, ATP1B2, DAAM2) combined with age and SARS-CoV-2 viral load achieved an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI, 0.82–0.94). A 3-gene nasal classifier (SLC5A5, CD200R1, FCER1A), in comparison, yielded an AUC of 0.74 (95% CI, 0.64–0.83). Notably, OLAH, the most strongly upregulated gene in both PBMC and nasal swab and recently implicated in severe viral infection pathogenesis, yielded AUCs of 0.86 (0.79–0.93) and 0.78 (95% CI, 0.69–0.86), respectively. Both peripheral blood classifiers demonstrated comparable performance in an independent contemporary cohort of vaccinated patients (AUCs 0.74–0.80).CONCLUSION Our parsimonious blood- and nasal-based classifiers accurately predicted COVID-19 mortality and merit further study as accessible prognostic tools to guide triage, resource allocation, and early therapeutic interventions.FUNDING NIH: 5R01AI135803-03, R35HL140026, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, 5T32DA018926-18, and K0826161611. National Institute of Allergy and Infectious Diseases, NIH: 3U19AI1289130, U19AI128913-04S1, and R01AI122220. National Center for Advancing Translational Sciences, NIH: UM1TR004528. The National Science Foundation: DMS2310836. The Chan Zuckerberg Biohub San Francisco.
Authors
Rithwik Narendra, Emily C. Lydon, Hoang Van Phan, Natasha Spottiswoode, Lucile P. Neyton, Joann Diray-Arce, IMPACC Network, COMET Consortium, EARLI Consortium, Patrice M. Becker, Seunghee Kim-Schulze, Annmarie Hoch, Harry Pickering, Patrick van Zalm, Charles B. Cairns, Matthew C. Altman, Alison D. Augustine, Steve Bosinger, Walter Eckalbar, Leying Guan, Naresh Doni Jayavelu, Steven H. Kleinstein, Florian Krammer, Holden T. Maecker, Al Ozonoff, Bjoern Peters, Nadine Rouphael, Ruth R. Montgomery, Elaine Reed, Joanna Schaenman, Hanno Steen, Ofer Levy, Sidney C. Haller, David Erle, Carolyn M. Hendrickson, Matthew F. Krummel, Michael A. Matthay, Prescott Woodruff, Elias K. Haddad, Carolyn S. Calfee, Charles R. Langelier
Abstract
BACKGROUND. Predictive biomarkers to guide chemotherapy decisions for metastatic castration resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance. METHODS. The CARD trial randomized subjects with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a pre-planned biomarker analysis, CTCs were isolated from blood samples obtained at baseline; cycle two, and end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA50 response rate (PRR) were assessed. RESULTS. High baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs 8.9 months; univariate HR, 2.16; 95% CI, 1.52 – 3.06; p < 0.001; multivariate HR, 1.56; 95% CI, 1.01 – 2.43; p = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel to ARPI. CONCLUSION. This preplanned biomarker analysis of CARD confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested. TRIAL REGISTRATION. CARD ClinicalTrials.gov number, NCT02485691. FUNDING. Funded by Sanofi and Epic Sciences.
Authors
Ossian Longoria, Jan Rekowski, Santosh Gupta, Nick Beije, Klaus Pantel, Eleni Efstathiou, Cora Sternberg, Daniel Castellano, Karim Fizazi, Bertrand Tombal, Adam Sharp, Oliver Sartor, Sandrine Macé, Christine Geffriaud-Ricouard, Richard Wenstrup, Ronald de Wit, Johann de Bono
Abstract
BACKGROUND Cisplatin is often the cytotoxic drug of choice for chemoradiation therapy (CRT) for head and neck squamous cell carcinoma (HNSCC), but it can lead to irreversible hearing loss. There may be similar oncologic outcomes but different toxicity profiles depending on whether cisplatin is given at 75–100 mg/m2 every 3 weeks or 30–40 mg/mg2 weekly. This study compares cisplatin-induced hearing loss in patients with HNSCC receiving similar cumulative doses of cisplatin administered either on higher-dose or lower-dose treatment schedules.METHODS Using the Enhancing Cancer Hearing Outcomes (ECHO) dataset from 5 academic centers, we conducted a multicenter retrospective cohort study of adults (≥18 years) with HNSCC receiving cisplatin-based CRT. Participants were grouped by cisplatin dose schedule: every 3 weeks (≥75 mg/m²) or weekly (<75 mg/m²). Hearing loss was assessed using American Speech-Language-Hearing Association (ASHA) and Common Terminology Criteria for Adverse Events (CTCAE) v5.0 threshold shift criteria based on audiograms obtained ≤120 days before and after treatment. Risk differences and predictors of hearing loss were evaluated using χ2 analyses and multivariate regression. Kaplan-Meier curves assessed overall and disease-free survival.RESULTS Among 564 participants (1,127 ears), lower-dose weekly cisplatin was associated with significantly lower incidence of hearing loss (ASHA criteria: 57% vs. 82%; CTCAE criteria: 39% vs. 69%). CTCAE grade ≥2 hearing loss occurred in 18% of the weekly group versus 50% of the 3-week group. Multivariate analysis confirmed treatment schedule as an independent predictor of ototoxicity. Two-year survival outcomes did not differ between groups.CONCLUSIONS Weekly low-dose cisplatin significantly reduced the incidence and severity of hearing loss without compromising survival, supporting its broader use in CRT for HNSCC.
Authors
Katharine A. Fernandez, Abu S. Chowdhury, Amanda Bonczkowski, Paul D. Allen, Maura H. Campbell, David S. Lee, Charvi Malhotra, Brandi R. Page, Deborah A. Mulford, Candice Evita Ortiz, Peter L. Santa Maria, Peter Kullar, Saad A. Khan, Shawn D. Newlands, Nicole C. Schmitt, Lisa L. Cunningham
Abstract
BACKGROUND. Blood donation increases the risk of iron deficiency, but its impact on brain iron, myelination, and neurocognition remains unclear. METHODS. This ancillary study enrolled 67 iron-deficient blood donors, 19–73 years of age, participating in a double-blind, randomized trial. After donating blood, positive and negative susceptibility were measured using Quantitative Susceptibility Mapping (QSM) magnetic resonance imaging (MRI) to estimate brain iron and myelin levels, respectively. Furthermore, neurocognitive function was evaluated using the NIH Toolbox, and neural network activation patterns were assessed during neurocognitive tasks using functional MRI (fMRI). Donors were randomized to intravenous iron repletion (one-gram iron) or placebo, and outcome measures repeated approximately four months later. RESULTS. Iron repletion corrected systemic iron deficiency and led to trends toward increased whole brain iron (P=0.04) and myelination (P=0.02), with no change in the placebo group. Although overall cognitive performance did not differ significantly between groups, iron-treated participants showed improved engagement of functional neural networks (e.g., memory pattern activation during speed tasks, P<0.001). Brain region-specific changes in iron and myelin correlated with cognitive performance: iron in the putamen correlated with working memory scores (P<0.01), and thalamic myelination correlated with attention and inhibitory control (P<0.01). CONCLUSION. Iron repletion in iron-deficient blood donors may influence brain iron, myelination, and function, with region-specific changes in iron and myelination linked to distinct cognitive domains. REGISTRATION. ClinicalTrials.gov NCT02990559. FUNDING. NIH grants HL133049, HL139489, and UL1TR001873.
Authors
Eldad A. Hod, Christian Habeck, Hangwei Zhuang, Alexey Dimov, Pascal Spincemaille, Debra Kessler, Zachary C. Bitan, Yona Feit, Daysha Fliginger, Elizabeth F. Stone, David Roh, Lisa Eisler, Stephen Dashnaw, Elise Caccappolo, Donald J. McMahon, Yaakov Stern, Yi Wang, Steven L. Spitalnik, Gary M. Brittenham
Abstract
BACKGROUND Icosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), reduces cardiovascular disease (CVD), but the mechanism remains elusive. We examined the effect of IPE supplementation on lipoprotein subclasses, lipidomes, and pro-atherogenic properties.METHODS Using 3 independent metabolomic platforms, we examined the effect of high-dose IPE supplementation for 28 days on fatty acid profiles, lipoprotein subclasses, lipidomes, and pro-atherogenic properties in normolipidemic volunteers (n = 38).RESULTS IPE supplementation increased lipoprotein EPA on average 4-fold within 7 days, returning to baseline after a 7-day washout. Notably, the incorporation displayed marked interindividual variance, negatively correlating with baseline levels. We identified persistent participant-specific lipoprotein fingerprints despite uniform IPE-induced lipidome remodeling across all lipoprotein classes. This remodeling resulted in reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids, resulting in reduced clinical risk markers, including triglyceride, remnant cholesterol, and apolipoprotein B (apoB) levels and 10-year CVD risk score. Of the pro-atherogenic properties tested, IPE significantly reduced apoB lipoprotein binding to proteoglycans, which correlated with lower apoB particle concentration, cholesterol content, and specific lipid species in LDL, including phosphatidylcholine 38:3 previously associated with CVD.CONCLUSION These findings highlight IPE’s rapid, uniform remodeling of lipoproteins and reduced proteoglycan binding, likely contributing to previously observed CVD risk reduction. Persistent interindividual lipidome signatures underscore the potential for personalized therapeutic approaches in atherosclerotic CVD treatment.TRIAL REGISTRATION NCT04152291.FUNDING Jenny and Antti Wihuri Foundation, Research Council of Finland, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Emil Aaltonen Foundation, Ida Montin Foundation, Novo Nordisk Foundation, Finnish Cultural Foundation, and Jane and Aatos Erkko Foundation.
Authors
Lauri Äikäs, Petri T. Kovanen, Martina B. Lorey, Reijo Laaksonen, Minna Holopainen, Hanna Ruhanen, Reijo Käkelä, Matti Jauhiainen, Martin Hermansson, Katariina Öörni
No posts were found with this tag.
